NM_000206.3:c.458_459delTCinsCG

Variant names:

• chrX-71110291-GA-CG
• NM_000206.3:c.458_459delTCinsCG
• IL2RG p.Ile153Thr

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM1 PM5

The NM_000206.3(IL2RG):​c.458_459delTCinsCG​(p.Ile153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I153N) has been classified as Pathogenic. The gene IL2RG is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 0 publications found

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

IL2RG Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to gamma chain deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Myriad Women’s Health
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285171 (HGNC:):

ACMG classification

Specifications for IL2RG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_000206.3 (IL2RG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000206.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71110292-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10022.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	NM_000206.3	MANE Select	c.458_459delTCinsCG	p.Ile153Thr	missense	N/A	NP_000197.1	P31785-1
	IL2RG	NM_001438870.1		c.458_459delTCinsCG	p.Ile153Thr	missense	N/A	NP_001425799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL2RG	ENST00000374202.7	TSL:1 MANE Select	c.458_459delTCinsCG	p.Ile153Thr	missense	N/A	ENSP00000363318.3	P31785-1
	ENSG00000285171	ENST00000646505.1		n.458_459delTCinsCG		non_coding_transcript_exon	Exon 4 of 12	ENSP00000496673.1	A0A2R8YE73
	IL2RG	ENST00000482750.6	TSL:5	c.458_459delTCinsCG	p.Ile153Thr	missense	N/A	ENSP00000421262.2	H0Y8J6

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-70330141;